NM_006897.3:c.497C>G

Variant names:

• chr12-54000685-C-G
• rs570351507
• NM_006897.3:c.497C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006897.3(HOXC9):​c.497C>G​(p.Ala166Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,414,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A166V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: HOXC9 NM_006897.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.97
• Publications: 0 publications found

Genes affected

HOXC9 (HGNC:5130): (homeobox C9) This gene belongs to the homeobox family of genes. The homeobox genes encode a highly conserved family of transcription factors that play an important role in morphogenesis in all multicellular organisms. Mammals possess four similar homeobox gene clusters, HOXA, HOXB, HOXC and HOXD, which are located on different chromosomes and consist of 9 to 11 genes arranged in tandem. This gene is one of several homeobox HOXC genes located in a cluster on chromosome 12. [provided by RefSeq, Jul 2008]

ENSG00000273049 (HGNC:):

HOXC6 (HGNC:5128): (homeobox C6) This gene belongs to the homeobox family, members of which encode a highly conserved family of transcription factors that play an important role in morphogenesis in all multicellular organisms. Mammals possess four similar homeobox gene clusters, HOXA, HOXB, HOXC and HOXD, which are located on different chromosomes and consist of 9 to 11 genes arranged in tandem. This gene, HOXC6, is one of several HOXC genes located in a cluster on chromosome 12. Three genes, HOXC5, HOXC4 and HOXC6, share a 5' non-coding exon. Transcripts may include the shared exon spliced to the gene-specific exons, or they may include only the gene-specific exons. Alternatively spliced transcript variants encoding different isoforms have been identified for HOXC6. Transcript variant two includes the shared exon, and transcript variant one includes only gene-specific exons. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.165964).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006897.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXC9	NM_006897.3	MANE Select	c.497C>G	p.Ala166Gly	missense	Exon 1 of 2	NP_008828.1	P31274

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXC9	ENST00000303450.5	TSL:1 MANE Select	c.497C>G	p.Ala166Gly	missense	Exon 1 of 2	ENSP00000302836.4	P31274
	ENSG00000273049	ENST00000513209.1	TSL:3	c.166+14675C>G		intron	N/A	ENSP00000476742.1	V9GYH0
	HOXC9	ENST00000508190.1	TSL:3	c.497C>G	p.Ala166Gly	missense	Exon 2 of 3	ENSP00000423861.1	P31274

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000533 AC: 1 AN: 187640 AF XY: 0.00000948

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000792

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1414592 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 702176

African (AFR) AF: 0.00 AC: 0 AN: 29708

American (AMR) AF: 0.00 AC: 0 AN: 37102

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24540

East Asian (EAS) AF: 0.0000273 AC: 1 AN: 36662

South Asian (SAS) AF: 0.00 AC: 0 AN: 81200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47800

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4278

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1095062

Other (OTH) AF: 0.00 AC: 0 AN: 58240

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.018
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	-0.051	T
MutationAssessor	Benign	0.55	N
PhyloP100		2.0
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.20
Sift	Benign	0.20	T
Sift4G	Benign	0.31	T
Polyphen		0.0010	B
Vest4		0.14
MutPred		0.38		Gain of catalytic residue at K169 (P = 0.0398)
MVP		0.98
MPC		0.99
ClinPred		0.20	T
GERP RS		4.2
Varity_R		0.12
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs570351507; hg19: chr12-54394469;